Sorafenib Combo Ups PFS but Toxicity Is High

Action Points

The combination of capecitabine and sorafenib led to a PFS of 6.4 mos compared with 4.1 mos for capecitabine alone in patients with advanced breast cancer.

Capecitabine with sorafenib was significantly more toxic than capecitabine alone with more grade 3 hand-foot syndrome.

Women with advanced breast cancer had 2-month improvement in progression-free survival (PFS) when the targeted drug sorafenib was added to chemotherapy, but toxicity levels were high, results of a placebo-controlled trial showed.

In this phase IIb study, patients who received sorafenib (Nexavar) and capecitabine (Xeloda) had a median PFS of 6.4 months compared with 4.1 months for patients treated with capecitabine and placebo.

However, the benefit came at a toxicity price too steep to be practical, investigators reported in the May 1 Journal of Clinical Oncology.

"The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients," José Baselga, MD, PhD, of Massachusetts General Hospital in Boston, and co-authors wrote. "A phase III confirmatory trial has been initiated with a reduced sorafenib dose."

Combination chemotherapy has demonstrated benefits over single-agent therapy in metastatic breast cancer but with increased toxicity. The advent of targeted therapies, particularly angiogenesis inhibitors, stirred optimism that effective but less toxic combinations might be found.

Sorafenib targets three VEGF receptor subtypes, as well as platelet-derived growth factor receptor, Raf kinase, c-Kit, and Flt-3. The potential to inhibit multiple pathways simultaneously provided a rationale to investigate the agent in breast cancer, the authors wrote in their introduction.

Interest in sorafenib led to a series of clinical trials to evaluate the targeted agent in combination with chemotherapy and hormonal therapy for advanced breast cancer. Baselga and coauthors reported findings from a trial of combination therapy in HER2-negative breast cancer.

Eligible patients had inoperable locally advanced or metastatic breast cancer and had received no more than one prior systemic chemotherapy regimen. Investigators in Spain, France, and Brazil randomized patients to capecitabine plus sorafenib or placebo. The primary endpoint was progression-free survival.

Enrollment began in August 2007 and ended in December 2008. Follow up continued to March 2009 for PFS, time to progression, and objective response rate and to July 2010 for safety and tolerability. The final analysis included 229 patients.

Patients were randomly assigned to ﬁrst- or second-line capecitabine (1,000 mg/m orally twice day) for days one to 14 of every 21-day cycle, along with sorafenib (400 mg orally twice a day) or placebo.

The 2.3-month difference in PFS achieved statistical significance (P=0.001) and the benefit was consistent across subgroups, including patients who received first- or second-line therapy.

Toxicities (all grades) occurred more often in the sorafenib arm versus placebo, including:

Hand-foot syndrome, 90% versus 66%

Diarrhea, 58% versus 30%

Mucosal inflammation, 33% versus 21%

Rash, 22% versus 8%

Hypertension, 18% versus 12%

Neutropenia, 13% versus 4%

Grade 3-4 toxicity occurred in a similar proportion of patients in each group with the exception of hand-foot syndrome, which was more common in the sorafenib arm compared with placebo (44% versus 14%).

More patients in the placebo arm discontinued because of disease progression (82% versus 63%), whereas withdrawal because of adverse events was more common in the sorafenib arm versus placebo (20% versus 9%).

The study had some limitations; specifically it was a phase IIb study with a small sample size. Also, there was potential for bias from participants who guessed treatment assignment based on toxicity, but the authors said that was not likely as sorafenib-induced hand-foot syndrome does not differ greatly from capecitabine-induced hand-foot syndrome.

The results "suggest a potential role for the combination of sorafenib plus capecitabine in HER2-negative advanced breast cancer but will need to be confirmed in the phase III setting," the authors concluded. "These results should not be considered practice changing."

The study was supported by the SOLTI research group, Onyx Pharmaceuticals, and Bayer.

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